PO.MCB03.01 · 分子与细胞生物学
敲除AKT1抑制PTEN缺失诱导的肝内胆管癌但不抑制小鼠肝细胞癌的发生
Deletion of AKT1 inhibits PTEN-loss induced intrahepatic cholangiocarcinoma but not hepatocellular carcinoma development in mice
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摘要 Abstract
中文摘要
肝癌是全球癌症相关死亡的第三大常见原因，其中肝细胞癌(HCC)和肝内胆管癌(ICC)是两种最常见的亚型。肝脏中缺失肿瘤抑制因子PTEN的小鼠(Pten loxP/loxP; albumin [Alb]-Cre-/+; LiPten)表现出随年龄增长逐渐发生的肝脂肪变性以及混合型HCC-ICC。Pten缺失导致丝氨酸/苏氨酸激酶AKT的激活。在迄今鉴定的三种AKT亚型中，AKT1亚型与细胞生长、增殖和存活的调控有关。在本研究中，我们通过构建一种新型双敲除小鼠模型(Pten loxP/loxP; Akt1 loxP/loxP; Alb-Cre-/+; LiPtenA1)研究了AKT1在介导PTEN缺失诱导的肝癌发生中的作用。与6月龄对照动物(Alb-Cre-/-)相比，喂食正常饲料的LiPten小鼠发生明显的肝肿大和弥漫性脂肪变性。LiPten动物中AKT1的缺失无法逆转脂肪变性，且LiPtenA1动物在体重或肝脏重量方面未表现出任何差异。在12月龄时，LiPten小鼠肝脏上发生肿瘤结节，具有脂肪变性、导管增生和扩张、HCC和ICC的显微特征。与LiPten小鼠一样，所有LiPtenA1动物在12月龄时均发生肿瘤结节。在显微镜下，LiPtenA1小鼠的肝脏表现出脂肪结节和HCC的特征。我们对ICC相关基因表达的初步分析以及肝脏ICC标志物的免疫组化染色显示，LiPtenA1小鼠的ICC表型显著减少。从LiPten小鼠的混合型HCC-ICC诱导性转变为LiPtenA1小鼠中以HCC为主的表型转换，提示AKT1在ICC发生中的作用，并有助于理解AKT亚型在调控肝脏肿瘤发生中的作用。
查看英文原文 English abstract
Liver cancer is the third most common cause of cancer-related mortality worldwide, with hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) representing the two most common subtypes. Mice lacking the tumor suppressor PTEN in the liver ( Pten loxP/loxP ; albumin [ Alb ] -Cre -/+ ; LiPten) display gradual, age-dependent development of hepatosteatosis and combined HCC-ICC. Pten loss results in activation of the serine/threonine kinase AKT. Of the three AKT isoforms identified to date, AKT1 isoform is implicated in regulation of cell growth, proliferation, and survival. In the present study, we investigated the role of AKT1 in mediating PTEN-loss induced liver cancer development by generating a novel double knockout mouse model ( Pten loxP/loxP ; Akt1 loxP/loxP ; Alb-Cre -/+ ; LiPtenA1). Compared to 6-month-old control animals ( Alb-Cre -/- ), LiPten mice fed normal chow developed marked hepatomegaly and diffuse steatosis. Loss of AKT1 in LiPten animals was unable to reverse steatosis, and LiPtenA1 animals did not exhibit any differences in body or liver weights. At 12 months old, LiPten mice developed tumor nodules on their livers, with microscopic features of steatosis, ductal proliferation and ectasia, HCC, and ICC. Like LiPten mice, all LiPtenA1 animals developed tumor nodules by 12 months of age. Microscopically, livers of LiPtenA1 mice displayed features of fatty nodules and HCC. Our preliminary analysis of expression of ICC-related genes and immunohistochemical staining of livers for ICC markers revealed significant reduction of ICC phenotype in LiPtenA1 mice. The induced phenotypic switch from combined HCC-ICC in LiPten mice to predominantly HCC in LiPtenA1 mice suggests a role for AKT1 in ICC development and contributes to the understanding of the role of AKT isoforms in regulating liver tumorigenesis.
利益披露 Disclosure
I. Slarve, None.